Sulfonamide derivatives

ABSTRACT

The present invention is directed to a new class of 6-sulfonamide quinoline and chromene derivative and to their use as androgen antagonists.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser. No. 60/456,316 filed Mar. 20, 2003.

FIELD OF THE INVENTION

The present invention is directed to a new class of quinolin-2-ones and chromen-2-ones (hereinafter “quinolines and chromenes”), to their use as androgen receptor antagonists, to medicinals containing these compounds and to their use to alleviate conditions associated with inappropriate activation of the androgen receptor.

BACKGROUND OF THE INVENTION

The androgen receptor (AR) is a member of the steroid receptor (SR) family of transcriptional regulatory proteins that transduces the signaling information conveyed by androgens. Upon androgen binding, the androgen receptor is released from the repressive effects of an Hsp 90-based regulatory complex, allowing the receptor to either activate or inhibit transcription of target genes in a hormone-dependent manner. In addition to the role the androgen receptor plays in male sex determination, its activation plays a critical role in the development and progression of benign prostate hyperplasia, prostate cancer, seborrhea, acne, premenstrual syndrome, lung cancer, ovarian polycyclic syndrome, hirsutism, and hair loss. Thus, the androgen receptor is an important target in multiple areas of drug discovery.

U.S. Pat. No. 6,017,924 discloses a class of non-steroidal compounds, pyridinoquinolines that have affinity for the androgen receptor. The '924 patent describes these compounds as being agonists, partial agonists, antagonists, and partial antagonists, etc. The '924 patent provides no guidance on how to achieve a specific biological effect (i.e. agonist versus antagonist). Agonists have the ability to masculinize females, whereas antagonists feminize males. Such side effects limit the potential applicability of androgen therapy.

PCT applications WO 01/16133 and WO 01/16139 also disclose non-steroidal compounds that have affinity for the androgen receptor. Examples of such structures include pyrazinoquinolines, oxazinoquinolines, and pyridinoquinolines. The PCT application does not disclose any 6-sulfonamido-quinolin-2-ones or 6-sulfonamido-chromen-2-ones.

PCT application WO 01/16108 discloses non-steroidal compounds having affinity for the androgen receptor. Like the '924 patent described above, the compounds are described as having both agonist and antagonist effects. Some of the compounds of the PCT application are quinolin-2-one derivatives. The PCT application does not disclose any 6-sulfonamido-quinolin-2-ones or 6-sulfonamido-chromen-2-ones.

While the prior art describes compounds having affinity for the androgen receptor, it does not describe how to achieve selectivity with respect to this affinity (i.e. agonist or antagonist). The physiological impact of this affinity is often an undesirable side effect, depending upon the gender of the patient. Thus a need exists in the art for androgen receptor antagonists.

SUMMARY OF THE INVENTION

In accordance with the present invention a new class of androgen antagonists have been discovered. These compounds may be represented by the following formula:

in which:

-   -   a. M is NZ or O;     -   b. Z is represented by H or C₁–C₄ alkyl;     -   c. R¹ is represented by hydrogen, (C₁–C₂)alkyl, optionally         substituted with one or more halogens, or (C₁–C₂)alkoxy,         optionally substituted with 1 or more halogens;     -   d. R² is absent, or may represent up to 2 substituents selected         from the group consisting of halogen, nitrile, hydroxy,         (C₁–C₄)alkyl, (C₂–C₄)alkenyl, (C₂–C₄)alkynyl, (C₁–C₄)alkoxy,         (C₁–C₂)alkyl substituted with 1 or more halogens, (C₁–C₂)alkoxy         substituted with one or more halogens, SR⁴, and NR⁴R⁵;     -   e. R⁴ is represented by hydrogen, optionally substituted phenyl,         (C₁–C₄)alkyl, or optionally substituted benzyl;     -   f. R⁵ is represented by optionally substituted phenyl,         optionally substituted heteroaryl, or optionally substituted         heterocyclic;     -   g. A and B are each independently represented by a substituent         selected from the group consisting of hydrogen, (C₁–C₆)alkyl         optionally substituted with one or more halogens,         (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, optionally substituted (C₃–C₈)         cycloalkyl, optionally substituted (C₅–C₈) cycloalkenyl,         optionally substituted phenyl, optionally substituted         cycloalkylphenyl, optionally substituted heterocyclic,         optionally substituted heteroaryl, (C₁–C₆)alkylR⁶,         —(CH₂)_(m)—R⁷—Y[—CH₂]_(n)—X—R⁸, —(CH₂)_(q)CHX¹X²;     -   h. R⁶ is represented by a substituent selected from the group         consisting of nitrile, OH, optionally substituted phenyl,         optionally substituted cyloalkylphenyl, optionally substituted         heterocyclic, optionally substituted heteroaryl, optionally         substituted (C₃–C₈) cycloalkyl, optionally substituted (C₅–C₈)         cycloalkenyl, SR⁴, NR⁴R⁵     -   i. R⁷ is absent, or is represented by a substituent selected         from the group consisting of optionally substituted (C₃–C₈)         cycloalkyl, optionally substituted (C₅–C₈) cycloalkenyl,         optionally substituted heteroaryl, optionally substituted         heterocyclic, and optionally substituted phenyl,     -   j. R⁸ is absent, or is represented by a substituent selected         from the group consisting of (C₁–C₆)alkyl optionally substituted         with one or more halogens, optionally substituted (C₃–C₈)         cycloalkyl, optionally substituted (C₅–C₈) cycloalkenyl,         optionally substituted heteroaryl, optionally substituted         heterocyclic, optionally substituted phenyl, and optionally         substituted cycloalkylphenyl;     -   k. m is an integer selected from 0, 1, 2, 3, or 4;     -   l. Y is absent, or is represented by O, C(O), C(O)O, CH₂C(O)O,         OH, SH, or S;     -   m. n is represented by an integer selected from 0, 1, 2, 3, or         4;     -   n. X is absent, or is represented by O, C(O), C(O)O, —CH₂C(O)O,         OH, SH or S     -   o. q is represented by an integer selected from 0, 1, 2, 3, or         4;     -   p. X¹ is represented by a substituent selected from the group         consisting of optionally substituted (C₃–C₈) cycloalkyl,         optionally substituted (C₅–C₈) cycloalkenyl, optionally         substituted heteroaryl, optionally substituted heterocyclic,         optionally substituted phenyl, and optionally substituted         cycloalkylphenyl;     -   q. X² is represented by a substituent selected from the group         consisting of optionally substituted (C₃–C₈) cycloalkyl,         optionally substituted (C₅–C₈) cycloalkenyl, optionally         substituted heteroaryl, optionally substituted heterocyclic,         optionally substituted phenyl, and optionally substituted         cycloalkylphenyl and;     -   r. the pharmaceutically acceptable salts, solvates, and prodrugs         thereof.

The compounds of Formula I are androgen receptor antagonists. The compounds will inhibit, or decrease, activation of the androgen receptor by androgens. The compounds can be used to treat, or alleviate, conditions associated with inappropriate activation of the androgen receptor. Examples of such conditions include, but are not limited to, acne, excess seborrhea secretion, alopecia, prostrate cancer, hirsutism, etc.

The invention is also directed to pharmaceutical compositions containing at least one of the compounds of Formula I, in an amount effective to decrease activation of the androgen receptor. In a further embodiment, the invention is directed to an article of manufacture containing a compound of Formula I, packaged for retail distribution, in association with instructions advising the consumer on how to use the compound to alleviate a condition associated with inappropriate activation of the androgen receptor. An additional embodiment is directed to the use of a compound of Formula I as a diagnostic agent to detect inappropriate activation of the androgen receptor.

In a further embodiment, the compounds of Formula I are used topically to induce and/or stimulate hair growth and/or to slow down hair loss. The compounds may also be used topically in the treatment of hyperseborrhoea and/or of acne.

DETAILED DESCRIPTION OF THE INVENTION

The headings within this document are only being utilized to expedite its review by the reader. They should not be construed as limiting the invention or claims in any manner.

Definitions and Exemplification

As used throughout this application, including the claims, the following terms have the meanings defined below, unless specifically indicated otherwise. The plural and singular should be treated as interchangeable, other than the indication of number:

-   -   a. “C₁–C₄ alkyl” and “lower alkyl” refers to a branched or         straight chained alkyl group containing from 1 to 4 carbon         atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,         isobutyl, etc.     -   b. “C₁–C₆ alkyl” refers to a branched or straight chained alkyl         group containing from 1 to 6 carbon atoms, such as methyl,         ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl,         isopentyl, n-hexyl, etc.     -   c. “halogen” refers to a chlorine, fluorine or bromine atom.     -   d. “C₁–C₂ alkyl substituted with one or more halogen atoms”         refers to a straight chained alkyl group containing 1 or 2         carbon atoms, i.e. methyl or ethyl, in which at least one         hydrogen atom is replaced with a halogen. Examples include         chloromethyl, difluoromethyl, trifluoromethyl, etc.     -   e. “lower alkoxy group” and “C₁–C₄ alkoxy” refers to a straight         or branched chain alkoxy group containing from 1 to 4 carbon         atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,         isobutoxy, etc.     -   f. “C₂–C₄ alkenyl” refers to a straight-chain or branched-chain         hydrocarbon radical containing from 2 to 4 carbon atoms and 1,         or more, carbon-carbon double bonds. Examples of alkenyl         radicals include ethenyl, propenyl, 1,4-butadienyl and the like.     -   g. “C₂–C₆ alkenyl” refers to a straight-chain or branched-chain         hydrocarbon radical containing from 2 to 6 carbon atoms and 1,         or more, carbon-carbon double bonds. Examples of alkenyl         radicals include ethenyl, propenyl, 1,4-butadienyl, pentenyl,         hexenyl and the like.     -   h. “C₂–C₄ alkynyl” refers to a straight-chain or branched-chain         hydrocarbon radical containing from 2 to 4 carbon atoms and         having 1, or more, carbon-carbon triple bonds. Examples of         alkynyl radicals include ethynyl, propynyl, butynyl and the         like.     -   i. “C₂–C₆ alkynyl” refers to a straight-chain or branched-chain         hydrocarbon radical containing from 2 to 6 carbon atoms and         having 1, or more, carbon-carbon triple bonds. Examples of         alkynyl radicals include ethynyl, propynyl, butynyl, pentynyl,         hexynyl and the like.     -   j. “(C₁–C₄)alkylnitrile” refers to a straight-chain or branched         chain alkyl group containing from 1 to 4 carbon atoms in which         at least one hydrogen atom is replaced with a C≡N moiety.     -   k. “(C₁–C₄)alkanol” refers to a straight-chain or branched         chained alkyl group containing from 1 to four carbon atoms group         in which at least one hydrogen atom is replaced with a hydroxy         function.     -   l. “optionally substituted phenyl” refers to a phenyl (C₆H₅)         which is substituted with up to 3 substituents, each substituent         is independently selected from the group consisting of halogen,         nitrile, hydroxy, (C₁–C₄)alkyl, (C₂–C₄)alkenyl, (C₂–C₄)alkynyl,         (C₁–C₄)alkoxy, (C₁–C₂)alkyl substituted with one or more         halogens, (C₁–C₂)alkoxy substituted with one or more halogens,         (C₁–C₄)alkylnitrile, (C₁–C₄)alkanol, SR⁴, and NR⁴R⁵. These         substituents may be the same or different and may be located at         any of the ortho, meta, or para positions.     -   m. “optionally substituted benzyl” refers to a benzyl         —CH₂—(C₆H₅) which is substituted with up to 3 substituents, each         substituent is independently selected from the group consisting         of halogen, nitrile, hydroxy, (C₁–C₄)alkyl, (C₂–C₄) alkenyl,         (C₂–C₄) alkynyl (C₁–C₄)alkoxy, (C₁–C₂)alkyl substituted with one         or more halogens, (C₁–C₂)alkoxy substituted with one or more         halogens, (C₁–C₄)alkylnitrile, (C₁–C₄)alkanol, SR⁴, and NR⁴R⁵.         These substituents may be the same or different and may be         located at any of the ortho, meta, or para positions.     -   n. (C₁–C₂)alkoxy substituted with one or more halogen atoms         refers to a straight chained alkoxy group containing 1 or 2         carbon atoms, ie, methoxy or ethoxy in which at least one         hydrogen atom is replaced with a halogen.     -   o. “heteroaryl” refers to aromatic ring having one, or more,         heteroatoms selected from oxygen, nitrogen and sulfur. More         specifically, it refers to a 5- or 6-, membered ring containing         1, 2, or 3 nitrogen atoms; 1 oxygen atom; 1 sulfur atom; 1         nitrogen and 1 sulfur atom; 1 nitrogen and 1 oxygen atom; 2         nitrogen atoms and 1 oxygen atom; or 2 nitrogen atoms and 1         sulfur atom. The 5-membered ring has 2 double bonds and the         6-membered ring has 3 double bonds. The term heteroaryl also         includes bicyclic groups in which the heteroaryl ring is fused         to a benzene ring, heterocyclic ring, a cycloalkyl ring, or         another heteroaryl ring. Examples of such heteroaryl ring         systems include, but are not limited to pyrrolyl, benzothienyl,         benzofuryl, quinolyl, isoquinolyl, furanyl, thienyl, imidazolyl,         oxazolyl, indolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl,         purinyl, quinolinyl, and isoquinolinyl.     -   p. “optionally substituted heteroaryl” refers to a heteroaryl         moiety as defined immediately above, in which up to 2 carbon         atoms of the heteroaryl moiety may be substituted with a         substituent, each substituent is independently selected from the         group consisting of halogen, nitrile, hydroxy, (C₁–C₄)alkyl,         (C₂–C₄)alkenyl, (C₂–C₄)alkynyl, (C₁–C₄)alkoxy, (C₁–C₂)alkyl         substituted with one or more halogens, (C₁–C₂)alkoxy substituted         with one or more halogens, (C₁–C₄)alkylnitrile , (C₁–C₄)alkanol,         SR⁴, and NR⁴R⁵. Further, any nitrogen atom of the heterocyclic         ring may be substituted with a (C₁–C₄)alkyl.     -   q. “heterocycle” or “heterocyclic ring” refers to any 3- or         4-membered ring containing a heteroatom selected from oxygen,         nitrogen and sulfur; or a 5-, 6-, 7-, 8-, 9-, or 10-membered         ring containing 1, 2, or 3 nitrogen atoms; 1 oxygen atom; 1         sulfur atom; 1 nitrogen and 1 sulfur atom; 1 nitrogen and 1         oxygen atom; 2 oxygen atoms in non-adjacent positions; 1 oxygen         and 1 sulfur atom in non-adjacent positions; or 2 sulfur atoms         in non-adjacent positions. The 5-membered ring has 0 to 1 double         bonds, the 6- and 7-membered rings have 0 to 2 double bonds, and         the 8, 9, or 10 membered rings may have 0, 1, 2, or 3 double         bonds. The term “heterocyclic” also includes bicyclic groups in         which any of the above heterocyclic rings is fused to a benzene         ring, a cyclohexane or cyclopentane ring or another heterocyclic         ring (for example tetrahydroquinolyl, dihydrobenzofuryl and the         like). Heterocyclics include: pyrrolidinyl, tetrahydrofuranyl,         tetrahydrothiophenyl, piperidinyl, piperazinyl, azepane,         azocane, morpholinyl, and quinolinyl.     -   r. “optionally substituted heterocyclic” refers to a         heterocyclic moiety as defined immediately above, in which up to         2 carbon atoms of the heterocycle moiety may be substituted with         a substituent, each substituent is independently selected from         the group consisting of halogen, nitrile, hydroxy, (C₁–C₄)alkyl,         (C₂–C₄) alkenyl, (C₂–C₄)alkynyl, (C₁–C₄)alkoxy, (C₁–C₂)alkyl         substituted with one or more halogens, (C₁–C₂)alkoxy substituted         with 1 or more halogens, (C₁–C₄)alkylnitrile, (C₁–C₄)alkanol,         (═O), SR⁴, and NR⁴R⁵. Further, any nitrogen atom of the         heterocyclic ring may be substituted with a (C₁–C₄)alkyl.     -   s. “C₃–C₈ cycloalkyl” refers to a saturated or partially         saturated monocyclic, bicyclic or tricyclic alkyl radical         wherein each cyclic moiety has about 3 to about 8 carbon atoms.         Examples of cyclcoalkyl radicals include cyclopropyl,         cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.     -   t. “optionally substituted “C₃–C₈ cycloalkyl” refers to a         cycloalkyl moiety as defined immediately above in which up to 3         hydrogen atoms of the cycloalkyl moiety may be replaced with a         substituent, each substituent is independently selected from the         group consisting of halogen, nitrile, hydroxy, (C₁–C₄)alkyl,         (C₂–C₄)alkenyl, (C₂–C₄)alkynyl, (C₁–C₄)alkoxy, (C₁–C₂)alkyl         substituted with one or more halogens, (C₁–C₂)alkoxy substituted         with one or more halogens, (C₁–C₄)alkylnitrile, (C₁–C₄)alkanol,         SR⁴, and NR⁴R⁵.     -   u. “C₅–C₈ cycloalkenyl” refers to a partially saturated         monocyclic, bicyclic or tricyclic alkyl radical containing 1, or         more, carbon-carbon double bonds, wherein each cyclic moiety has         about 5 to about 8 carbon atoms. Examples of cyclcoalkenyl         radicals include cyclopentenyl, cyclohexenyl, and the like     -   v. “optionally substituted “C₅–C₈ cycloalkenyl” refers to a         cycloalkenyl moiety as defined immediately above, in which up to         3 hydrogen atoms of the cycloalkenyl moiety may be replaced with         a substituent, each substituent is independently selected from         the group consisting of halogen, nitrile, hydroxy, (C₁–C₄)alkyl,         (C₂–C₄)alkenyl, (C₂–C₄)alkynyl , (C₁–C₄)alkoxy, (C₁–C₂)alkyl         substituted with one or more halogens, (C₁–C₂)alkoxy substituted         with one or more halogens, (C₁–C₄)alkylnitrile, (C₁–C₄)alkanol,         SR⁴, and NR⁴R⁵.     -   w. “cycloalkylphenyl” refers to a phenyl ring in which two         carbon atoms of the phenyl ring complete a cyclobutyl,         cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl ring.         Examples of such cycloalkylphenyl moieties include: indanyl,         tetrahydronapthyl, and the like.     -   x. “optionally substituted cycloalkylphenyl” refers to a         cycloalkylphenyl moiety as described above, in which up to 3         hydrogen atoms of the cycloalkylphenyl moiety may be replaced by         a substituent, each substituent is independently selected from         the group consisting of halogen, nitrile, hydroxy, (C₁–C₄)alkyl,         C₂–C₄ alkenyl, C₂–C₄ alkynyl, (C₁–C₄)alkoxy, (C₁–C₂)alkyl         substituted with one or more halogens, (C₁–C₂)alkoxy substituted         with one or more halogens, (C₁–C₄)alkylnitrile, (C₁–C₄)alkanol,         SR⁴, and NR⁴R⁵.     -   y. “androgen” refers to testosterone and its precursors and         metabolites, and 5-alpha reduced androgens, including but not         limited to dihydrotestosterone. Androgen refers to androgens         from the testis, adrenal gland, and ovaries, as well as all         forms of natural, synthetic and substituted or modified         androgens.     -   z. “pharmaceutically acceptable salts” is intended to refer to         either pharmaceutically acceptable acid addition salts” or         “pharmaceutically acceptable basic addition salts” depending         upon actual structure of the compound.     -   aa. “pharmaceutically acceptable acid addition salts” is         intended to apply to any non-toxic organic or inorganic acid         addition salt of the base compounds represented by Formula I or         any of its intermediates. Illustrative inorganic acids which         form suitable salts include hydrochloric, hydrobromic,         sulphuric, and phosphoric acid and acid metal salts such as         sodium monohydrogen orthophosphate, and potassium hydrogen         sulfate. Illustrative organic acids, which form suitable salts         include the mono-, di-, and tricarboxylic acids. Illustrative of         such acids are for example, acetic, glycolic, lactic, pyruvic,         malonic, succinic, glutaric, fumaric, malic, tartaric, citric,         ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic,         phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic,         p-toluenesulfonic acid, and sulfonic acids such as methane         sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can         exist in either a hydrated or substantially anhydrous form. In         general, the acid addition salts of these compounds are soluble         in water and various hydrophilic organic solvents, and which in         comparison to their free base forms, generally demonstrate         higher melting points.     -   bb. “pharmaceutically acceptable basic addition salts” is         intended to apply to any non-toxic organic or inorganic basic         addition salts of the compounds represented by Formula I, or any         of its intermediates. Illustrative bases which form suitable         salts include alkali metal or alkaline-earth metal hydroxides         such as sodium, potassium, calcium, magnesium, or barium         hydroxides; ammonia, and aliphatic, alicyclic, or aromatic         organic amines such as methylamine, dimethylamine,         trimethylamine, and picoline.     -   cc. “prodrug” refers to compounds that are rapidly transformed         in vivo to yield the parent compound of the above formulas, for         example, by hydrolysis in blood. A thorough discussion is         provided in T. Higuchi and V. Stella, “Pro-drugs as Novel         Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and         in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,         American Pharmaceutical Association and Pergamon Press, 1987,         both of which are incorporated herein by reference.     -   dd. “compound of Formula I” “compounds of the invention” and         “compounds” are used interchangeably throughout the application         and should be treated as synonoms.     -   ee. “patient” refers to warm blooded animals such as, for         example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs,         monkeys, chimpanzees, and humans.     -   ff. “treat” refers to the ability of the compounds to either         relieve, alleviate, or slow the progression of the patient's         disease (or condition) or any tissue damage associated with the         disease.

Some of the compounds of Formula I will exist as optical isomers. Any reference in this application to one of the compounds represented by Formula I is meant to encompass either a specific optical isomer or a mixture of optical isomers (unless it is expressly excluded). The specific optical isomers can be separated and recovered by techniques known in the art such as chromatography on chiral stationary phases or resolution via chiral salt formation and subsequent separation by selective crystallization. Alternatively utilization of a specific optical isomer as the starting material will produce the corresponding isomer as the final product.

In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

Some of the compounds of Formula I are based upon a 6-sulfonamido-quinolin-2-one nucleus. To further exemplify the invention this ring is depicted below along with its numbering system:

Position 1 of the quinoline nucleus contains a nitrogen atom. This nitrogen atom may be substituted with a lower alkyl group as described above. Position 6 of the quinoline ring will always be substituted with a SO₂ moiety as depicted in FIG. 1. Any of positions 3, 5, 7, or 8 of the quinoline nucleus may optionally be substituted with a substituent from the list described for R². Up to two of these positions may be substituted. Position 4 of the quinoline nucleus may optionally be substituted with 1 of the halogenated lower alkyl or alkoxy moieties described for R¹ above. Typically, Position 4 will be substituted with a trifluoromethyl function.

The remaining compounds of Formula I are based upon a 6-sulfonamido-2-oxo-chromene nucleus. To further exemplify the invention, this ring is depicted below along with its numbering system:

Position 1 of the chromene nucleus contains an oxygen atom. Position 6 of the chromene ring will always be substituted with a SO₂ moiety as depicted in FIG. 1. Any of Positions 3, 5, 7, or 8 of the chromene nucleus may optionally be substituted with a substituent from the list described for R₂. Up to two of these positions may be substituted. Position 4 of the chromene nucleus may optionally be substituted with one of the halogenated lower alkyl or alkoxy moieties described for R¹ above. Typically, Position 4 will be substituted with a trifluoromethyl function.

More specific embodiments of the invention are directed to compounds of Formula I in which:

-   -   a. M is NZ, in which Z is H; R¹ is trifluoromethyl, R² is         absent, B is hydrogen, and A is represented by phenyl, which may         be optionally substituted.     -   b. M is NZ, in which Z is H, R¹ is trifluoromethyl, R² is         absent, B is hydrogen, or C₁–C₆ alkyl and A is C₁–C₆ alkyl, more         typically C₁–C₃ alkyl.     -   c. M is NZ, in which Z is H, R¹ is trifluoromethyl, R² is         absent, B is hydrogen, A is C₁–C₆ alkyl R⁶, and more         specifically a C₁–C₃ alkylphenyl ring.     -   d. M is NZ, in which Z is H, R¹ is trifluoromethyl, R² is         absent, B is hydrogen, A is C₁–C₆ alkylR⁶, and R⁶ is phenyl,         which has been substituted with trifluoromethyl, or C₁–C₄alkyl,         more specifically ethyl.     -   e. M is NZ in which Z is H, R¹ is trifluoromethy, R² is absent,         B is hydrogen, A is C₁–C₆ alkylR⁶, and R⁶ is cycloalkenyl,         typically cyclohexenyl.     -   f. M is NZ in which Z is H, R¹ is trifluoromethyl, R² is absent,         B is hydrogen, A is C₁–C₆ alkylR⁶, and R⁶ is cycloalkylphenyl.     -   g. M is NZ in which Z is H, R¹ is trifluoromethyl, R² is absent,         B is hydrogen, A is C₁–C₆ alkylR⁶, and R⁶ is heterocyclic.     -   h. M is NZ in which Z is H, R¹ is trifluoromethyl, R² is absent,         B is hydrogen, A is C₁–C₆ alkylR⁶, and R⁶ is heteroaryl.         Synthesis

The compounds of formula can be prepared using methods analogous to those known in the art for the preparation of sulfonamides. The reader's attention is directed to J. March, Advanced Organic Chemistry, 3^(rd) edition, page 445, John Wiley & Sons (1985) for a more detailed discussion of such synthesis. Scheme I below provides a general overview:

As depicted above, one of the starting materials is an appropriately substituted quinolin-2-one or 2-oxo-chromene (i.e. R¹, R², and M are as in desired compound) that has been functionalized at the 6-position with a sulfonyl chloride moiety (Formula II). These compounds may be produced by introducing the sulfonyl chloride moiety into the 6-postion of the quinolin-2-ones and 2-oxo-chromenes by chlorosulfonation with chlorosulfonic acid at about 140° C. These reactions are described in more detail in the working examples. The reader's attention is also directed to Furniss et al, Vogel's Textbook of Practical Organic Chemistry, 5^(th) Edition, pages 877–879, where such reactions are described in detail.

The other starting material is an appropriately substituted amine as described by Formula III (i.e. A and B are as in final compound). These amines can typically be purchased from Aldrich, which has an office located in St. Louis, Mo. USA. Further information may be obtained from Aldrich at, www.sigmaaldrich.com

The sulfonamides derivatives of Formula I are prepared by reacting the sulfonyl chloride derivative of Formula II with the appropriate amine as described by Formula III in the presence of a non-nucleophilic base, such as pyridine or diisopropylethylamine, at about room temperature in an aprotic solvent, such as, N,N′-dimethylformamide. The reaction is allowed to proceed to completion, which is typically accomplished in from 2 to 24 hours. If desired, the compounds can be isolated and purified using techniques known in the art such as extraction and flash chromatography. These reactions are described in detail in the working examples.

Medical and Cosmetic Uses

The compounds of Formula I are androgen receptor antagonists. They can be used to alleviate any condition associated with inappropriate activation of the androgen receptor. Examples of such conditions include prostate carcinomas, benign hyperplasia of the prostate, acne, hirsutism, seborrhoea, alopecia, premenstrual syndrome, lung cancer, and precocious puberty.

In order to exhibit the therapeutic properties described above, the compounds need to be administered in a quantity sufficient to inhibit activation of the androgen receptor. This antagonistic amount can vary depending upon the particular disease/condition being treated, the severity of the patient's disease/condition, the patient, the particular compound being administered, the route of administration, and the presence of other underlying disease states within the patient, etc. When administered systemically, the compounds typically exhibit their effect at a dosage range of from about 0.1 mg/kg/day to about 100 mg/kg/day for any of the diseases or conditions listed above. Repetitive daily administration may be desirable and will vary according to the conditions outlined above.

The compounds of the present invention may be administered by a variety of routes. They are effective if administered orally. The compounds may also be administered parenterally (i.e. subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally), rectally, or topically.

In a typical embodiment, the compounds are administered topically. Topical administration is especially appropriate for hirsutism, alopecia, acne and hyperseborhhea. The dose will vary, but as a general guideline, the compound will be present in a dermatologically acceptable carrier in an amount of from 0.1 to 10 w/w % and the dermatological preparation will be applied to the affected area from 1 to 4 times daily. “Dermatologically acceptable” refers to a carrier which may be applied to the skin or hair, and which will allow the drug to diffuse to the site of action. More specifically, it refers to the site where inhibition of activation of an androgen receptor is desired. In a further embodiment, the compounds are used topically to relieve alopecia, especially androgenic alopecia. Androgens have a profound effect on both hair growth and hair loss. In most body sites, such as the beard and pubic skin, androgens stimulate hair growth by prolonging the growth phase of the hair cycle (anagen) and increasing follicle size. Hair growth on the scalp does not require androgens but, paradoxically, androgens are necessary for balding on the scalp in genetically predisposed individuals (androgenic alopecia) where there is a progressive decline in the duration of anagen and in hair follicle size. Men castrated before puberty fail to grow beards and do not go bald. If subsequently treated with testosterone about one third of male castrates will show balding. Androgeneic alopecia is also common in women where it usually present as a diffuse hair loss rather than showing the patterning seen in men.

As used in this application “alopecia” refers to partial or complete hair loss on the scalp. The compounds will typically be used to alleviate androgenic alopecia. This condition afflicts both men and women. In males, the hair loss begins in the lateral frontal areas or over the vertex. For females, it is typically associated with thinning of the hair in the frontal and parietal regions. Complete hair loss in females is rare.

While the compounds will most typically be used to alleviate androgenic alopecia, the invention is not limited to this specific condition. The compounds may be used to alleviate any type of alopecia. Examples of non-androgenic alopecia include alopecia areata, alopecia due to radiotherapy or chemotherapy, scarring alopecia, stress related alopecia, etc.

Thus, the compounds can be applied topically to the scalp and hair to prevent, or alleviate balding. Further, the compound can be applied topically in order to induce or promote the growth of hair on the scalp.

In a further embodiment of the invention, a compound of Formula I is applied topically in order to prevent the growth of hair in areas where such hair growth is not desired. One such use will be to alleviate hirsutism. Hirsutism is excessive hair growth in areas that typically do not have hair (i.e. a female face). Such inappropriate hair growth occurs most commonly in women and is frequently seen at menopause. The topical administration of the compounds will alleviate this condition leading to a reduction, or elimination of this inappropriate, or undesired, hair growth.

The compounds may also be used topically to decrease seborrhea production and more specifically to alleviate hyperseborrhoea (oily skin). Likewise the compounds can be used topically alleviate acne.

Formulations

If desired, the compounds can be administered directly without any carrier. However, to ease administration, they will typically be formulated into pharmaceutical carriers. Likewise, they will most typically be formulated into dermatological, or cosmetic carriers. In this application the terms “dermatological carrier” and “cosmetic” carrier are being used interchangeably. They refer to formulations designed for administration directly to the skin or hair.

Pharmaceutical and cosmetic compositions can be manufactured utilizing techniques known in the art. Typically an antagonistic amount of the compound will be admixed with a pharmaceutically/cosmetically acceptable carrier.

For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations.

In another embodiment, the compounds of Formula I can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent, which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.

For parenteral administration the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the art. When the compounds are being administered intrathecally, they may also be dissolved in cerebrospinal fluid as is known in the art.

The compounds of this invention will typically be administered topically. As used herein, topical refers to application of the compounds (and optional carrier) directly to the skin or hair. The topical composition according to the present invention can be in the form of solutions, lotions, salves, creams, ointments, liposomes, sprays, gels, roller sticks, or any other method using micelles and pharmaceutically acceptable penetration enhancers

Thus, a further embodiment relates to cosmetic or pharmaceutical compositions, in particular dermatological compositions, which comprise at least one of the compounds corresponding to Formula I above. Such dermatological compositions will contain from 0.001% to 10% w/w % of the compounds in admixture with a dermatologically acceptable carrier, and more typically, from 0.1 to 5 w/w % of the compounds. Such compositions will typically be applied from 1 to 4 times daily.

The compositions according to the invention can also consist of solid preparations constituting cleansing soaps or bars. These compositions are prepared according to the usual methods.

The compounds can also be used for the hair in the form of aqueous, alcoholic or aqueous-alcoholic solutions, or in the form of creams, gels, emulsions or mousses, or alternatively in the form of aerosol compositions also comprising a propellant under pressure. The composition according to the invention can also be a hair care composition, and in particular a shampoo, a hair-setting lotion, a treating lotion, a styling cream or gel, a dye composition (in particular an oxidation dye composition) optionally in the form of coloring shampoos, restructuring lotions for the hair, a permanent-waving composition (in particular a composition for the first stage of a permanent-waving operation), a lotion or gel for preventing hair loss, etc. The amounts of the various constituents in the dermatological compositions according to the invention are those conventionally used in the fields considered.

The medicinals and cosmetics containing the compounds of the invention will typically be packaged for retail distribution (i.e. an article of manufacture). Such articles will be labeled and packaged in a manner to instruct the patient how to use the product. Such instructions will include the condition, which may be treated, duration of treatment, dosing schedule, etc.

The compounds of Formula I may also be admixed with any inert carrier and utilized in laboratory assays in order to determine the concentration of the compounds within the serum, urine, etc., of the patient as is known in the art. The compounds may also be used as a research tool.

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention. The following examples and biological data is being presented in order to further illustrate the invention. This disclosure should not be construed as limiting the invention in any manner.

EXAMPLES Materials and Methods

Column chromatography was carried out on SiO₂ (40–63 mesh). LCMS data were obtained using a Phenomenex Mercury Luna 3 μ C₁₈ column (2×10 mm, flow rate=1.5 mL min⁻¹) eluting with a 5% MeCN in H₂O-MeCN solution (4:1 to 1:4) containing 0.1% HCO₂H over 2.55 minutes and diode array detection. The mass spectra were obtained employing an electrospray ionisation source in the positive (ES⁺) & negative (ES⁻) ion modes. Preparative mass-directed liquid chromatographic purification was carried out utilizing a Waters Xterra 5μ C₁₈ column (19×50 mm, flow rate=20 mL min⁻¹) eluting with a 5% MeCN in H₂O-MeCN solution (4:1 to 1:4) containing 0.1% HCO₂H over 7 minutes and diode array detection. ¹H NMR spectra were recorded at 400 MHz on a Varian Mercury spectrometer at 27° C. The deuterated solvent was used as the lock, while the residual solvent peak was employed as internal reference. Acronyms: DMAP=4-Dimethylaminopyridine; HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; NMP=1-Methyl-2-pyrrolidinone; PE=Petroleum ether (B.p.=60–80° C.); RT=Retention time.

Preparation of Starting Materials

Preparation 1: 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride

KOH (10.54 g, 188.0 mmol) was added to a solution of 4-trifluoromethyl-1H-quinolin-2-one (4.00 g, 18.8 mmol) in DMF (160 mL). After 1 hour, the mixture was treated with MeI (11.7 mL, 188.0 mmol), then stirring was continued overnight. EtOAc (200 mL) was added, followed by saturated aqueous NH₄Cl to adjust the aqueous pH to 6.5. After separation of the layers, the aqueous phase was extracted further with EtOAc (2×200 mL). The combined organic extracts were washed with H₂O (200 mL) and brine (200 mL), before being dried (MgSO₄). Filtration, solvent evaporation, and column chromatography (PE-EtOAc, 4:1 to 7:3) yielded 1-methyl-4-trifluoromethyl-1H-quinolin-2-one (4.00 g, 94%): δ_(H) ((CD₃)₂SO)=3.65 (s, 3H), 7.10 (s, 1H), 7.40 (t, 1H), 7.65–7.80 (m, 3H). This compound (8.70 g, 38.3 mmol) was added portionwise with stirring over 20 min to fuming H₂SO₄ (30% oleum, 17.5 mL) at 84° C. The bath temperature was raised to 120° C. for 1 hour, before being cooled back down to 20° C. Thereupon, the mixture was added slowly to saturated aqueous NaCl (60 mL) and stirred for 30 min. The solid produced was collected & dried under vacuum at 50° C. to give sodium 1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonate: δ_(H)((CD₃)₂SO)=3.65 (s, 3H), 7.10 (s, 1H), 7.65 (d, 1H), 7.95 (dd, 1H), 8.00 (d, 1H). This compound was suspended in MeCN-sulfolane (1:1, 52 mL), before being treated with POCl₃ (18.8 mL, 201.7 mmol). The mixture was heated to 88° C. for 1.5 hours, before being cooled to 20° C. over 0.5 hour. On cooling to <5° C., ice cold H₂O (128 mL) was added, the temperature being maintained below 7° C. The mixture was stirred at 0° C. for 20 minutes, then the solid formed was collected and washed with H₂O to afford, after drying, the title compound (9.62 g, 73%): δ_(H) (CDCl₃)=3.80 (s, 3H), 7.25 (s, 1H), 7.65 (d, 1H), 8.25 (dd, 1H), 8.50 (d, 1H). Preparation 2: 2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonyl chloride

Sulfonation of 4-trifluoromethylchromen-2-one (5.00 g, 23.3 mmol), followed by NaCl treatment, as described in Preparation 1, produced sodium 2-oxo-4-trifluoromethyl-2H-chromene-6-sulfonate: δ_(H) ((CD₃)₂SO)=7.10 (s, 1H), 7.45 (d, 1H), 7.90 (dd, 1H), 7.95 (d, 1H). Reaction of this compound with POCl₃ (10.3 mL, 110.5 mmol) provided the title compound (5.48 g, 75%): δ_(H) (CDCl₃)=7.00 (s, 1H), 7.70 (d, 1H), 8.30 (dd, 1H), 8.40 (d, 1H). Preparation 3: 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride

4-Trifluoromethyl-1H-quinolin-2-one (5.00 g, 23.5 mmol) was treated with ClSO₃H (3.1 mL, 47.0 mmol) at 0° C. The mixture was then heated with stirring to 140° C. for 7 hours. On cooling, ice-cold H₂O (50 mL) was added. The solid produced was collected and dried to give the title compound (2.93 g, 41%): δ_(H) (CDCl₃)=7.20 (s, 1H), 7.60 (d, 1H), 8.20 (dd, 1H), 8.50 (d, 1H).

Preparation of Compounds of Formula I Example 1

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid phenylamide

A solution of 1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (Preparation 1, 65 mg, 200 μmol) in anhydrous DMF (1.5 mL) was contacted with PhNH₂ (19 μL, 210 μmol), employing pyridine (17 μL, 220 μmol) as base), before being stirred overnight under N₂. The reaction mixture was diluted with EtOAc (70 mL), before being washed with H₂O (30 mL), 1 M HCl (30 mL), H₂O (30 mL), saturated aqueous NaHCO₃ (30 mL), H₂O (30 mL), & brine (30 mL). After drying (MgSO₄), the organic phase was filtered & concentrated to give a residue that was recrystallised from EtOAc-PE to furnish the title compound (39 mg, 50%): δ_(H) ((CD₃)₂SO)=3.60 (s, 3H), 7.00 (s, 1H), 7.10 (d, 2H), 7.15–7.20 (m, 3H), 7.80 (d, 1H), 8.00–8.05 (m, 2H); m/z (ES⁺)=383.1 [M+H]⁺.

Example 2

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid phenylamide

Following the same procedure as Example 1, condensation of 2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (Preparation 3, 50 mg, 160 μmol) with PhNH₂ (15 μL, 168 μmol), employing pyridine (14 μL, 168 μmol) as base, gave the title compound (11 mg, 17%): δ_(H) ((CD₃)₂SO)=7.00 (s, 1H), 7.05–7.10 (m, 3H), 7.20 (m, 2H), 7.50 (d, 1H), 7.90 (dd, 1H), 8.00 (d, 1H); m/z (ES₊)=369.1 [M+H]⁺.

Example 3

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid benzylamide

Condensation of 2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (Preparation 3, 16 mg, 51 μmol) with BnNH₂ (7 μL, 54 μmol), employing NEt₃ (8 μL, 57 μmol) as base as delineated in Example 1, gave the title compound (18 mg, 90%): δ_(H) ((CD₃)₂SO) =4.00 (d, 2H), 7.05 (s, 1H), 7.10–7.20 (m, 5H), 7.50 (d, 1H), 7.95 (dd, 1H), 8.00 (d, 1H), 8.30 (t, 1H); m/z (ES⁻)=381.0 [M−H]⁻.

Examples 4–67

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid amides, 2-oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid amides, (Table 1)

These compounds were prepared by solution phase parallel synthesis. The appropriate amine as described by Formula III (30 μL of a 0.33 M solution in NMP, 9.9 μmol), i-Pr₂NEt (20 μL of a 0.50 M solution in NMP, 10.0 μmol), & the sulfonyl chloride of Formula II (50 μL of a 0.20 M solution in NMP, 10.0 μmol) were mixed together in 1 well of a 96-well plate using an automated liquid handler. After agitating for 66 h, the solvents were evaporated off under reduced pressure & DMF (50 μL) was added. To ensure dissolution, the mixture was shaken, before being treated with EtOAc (450 μL). Using automated liquid-liquid extraction equipment, the solution was washed with H₂O (150 μL) & 1% aqueous NaHCO₃ (150 μL). The organic layer was concentrated to furnish the compounds displayed in Table 1.

Example CHEMISTRY Name RT Base Peak 4

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid butylethylamide 1.98 391.2 [M + H]⁺ 5

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid butyl(2-hydroxyethyl)-amide 1.70 407.2 [M + H]⁺ 6

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid benzyl(2-hydroxyethyl)-amide 1.72 441.2 [M + H]⁺ 7

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (2-hydroxyethyl)-pentylamide 1.78 421.2 [M + H]⁺ 8

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid butyimethylamide 1.90 377.2 [M + H]⁺ 9

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid dibenzylamide 2.16 487.2 [M + H]⁺ 10

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid benzylethylamide 2.00 425.2 [M + H]⁺ 11

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid methylphenethylamide 1.98 425.2 [M + H]⁺ 12

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid methylphenylamide 1.85 395.2 [M − H]⁻ 13

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid m-tolylamide 1.84 395.2 [M − H]⁻ 14

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid p-tolylamide 1.80 395.2 [M − H]⁻ 15

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (4-ethynylphenyl)amide 1.81 405.2 [M − H]⁻ 16

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (3-ethylphenyl)amide 1.88 409.2 [M − H]⁻ 17

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (4-ethylphenyl)amide 1.91 409.2 [M − H]⁻ 18

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (2,6-dimethylphenyl)amide 1.85 409.2 [M − H]⁻ 19

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid(2-hydroxymethylphenyl)amide 1.61 411.2 [M − H]⁻ 20

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (2-methoxyphenyl)amide 1.78 411.2 [M − H]⁻ 21

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (4-cyanomethylphenyl)amide 1.70 420.2 [M − H]⁻ 22

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid indan-5-ylamide 1.93 421.2 [M − H]⁻ 23

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid indan-4-ylamide 1.89 421.2 [M − H]⁻ 24

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (3-acetylphenyl)amide 1.68 423.2 [M − H]⁻ 25

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (4-isopropylphenyl)amide 2.00 423.2 [M − H]⁻ 26

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid benzo[1,3]dioxol-5-ylamide 1.75 425.1 [M − H]⁻ 27

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (4-methylbipheny-3-yl)amide 2.00 471.2 [M − H]⁻ 28

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydro-quinoline-6-sulfonic acid [3-(1-hydroxyethyl)phenyl]-amide 1.55 425.2 [M − H]⁻ 29

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (3-methylsulfanylphenyl)amide 1.85 427.1 [M − H]⁻ 30

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (5-fluoro-2-methylphenyl)amide 1.82 413.2 [M − H]⁻ 31

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (4-chlorophenyl)amide 1.89 415.4 [M − H]⁻ 32

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid isoquinolin-3-ylamide 1.74 434.1 [M + H]⁺ 33

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid quinolin-3-ylamide 1.68 434.1 [M + H]⁺ 34

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid quinolin-8-ylamide 1.86 434.2 [M + H]⁺ 35

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (4-cyano-5-methylsulfanyl-2H-pyrazol-3-yl)amide 1.78 442.1 [M − H]⁻ 36

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (3,5-dimethoxyphenyl)-amide 1.77 441.2 [M − H]⁻ 37

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (3-isopropoxyphenyl)-amide 1.88 439.2 [M − H]⁻ 38

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (3-difluoromethoxy-phenyl)amide 1.85 447.1 [M − H]⁻ 39

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (3-trifluoromethylphenyl)-amide 1.90 449.1 [M − H]⁻ 40

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic(4-methyl-2-oxo-2H-chromen-7-yl)amide 1.72 463.2 [M − H]⁻ 41

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (3-trifluoromethoxy-phenyl)amide 1.96 465.1 [M − H]⁻ 42

[4-(1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonylamino)phenyl]aceticacid ethyl ester 1.79 467.2 [M − H]⁻ 43

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (3-benzylphenyl)amide 1.97 471.2 [M − H]⁻ 44

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (4-ethoxyphenyl)amide 1.82 425.2 [M − H]⁻ 45

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (3,5-di-tert-butylphenyl)amide 2.26 493.3 [M − H]⁻ 46

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid benzyl(4-methoxy-phenyl)amide 2.03 503.2 [M + H]⁺ 47

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid [4-(3-trifluoromethylpyrazol-1-yl)phenyl]amide 1.92 515.2 [M − H]⁻ 48

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (3-methoxyphenyl)amide 1.76 411.2 [M − H]⁻ 49

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (3,3-dimethylbutyl)amide 1.89 389.2 [M − H]⁻ 50

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid phenethylamide 1.85 409.2 [M − H]⁻ 51

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid 4-methylbenzylamide 1.85 409.2 [M − H]⁻ 52

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid 2-methylbenzylamide 1.82 409.2 [M − H]⁻ 53

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (2-cyclohex-1-enylethyl)amide 1.97 413.2 [M − H]⁻ 54

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (2-thiophen-2-ylethyl)amide 1.78 415.1 [M − H]⁻ 55

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid indan-1-ylamide 1.86 421.2 [M − H]⁻ 56

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (2-phenylpropyl)amide 1.85 423.2 [M − H]⁻ 57

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (4-phenylbutyl)amide 1.95 437.2 [M − H]⁻ 58

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid [2-(2-methoxyphenyl)ethyl]amide 1.85 439.2 [M − H]⁻ 59

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid 5-chloro-2-fluorobenzylamide 1.85 447.1 [M − H]⁻ 60

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid [2-(1H-indol-3-yl)ethyl]amide 1.75 448.2 [M − H]⁻ 61

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid (2-tert-butylsulfanylethyl)amide 1.87 421.2 [M − H]⁻ 62

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid 2-trifluoromethyl-benzylamide 1.88 463.2 [M − H]⁻ 63

1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonicacid [2-(2-chloro-6-fluorobenzylsulfanyl)ethyl]-amide 1.97 507.1 [M − H]⁻ 64

2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid(pyridin-3-ylmethyl)amide 1.18 385.1 [M + H]⁺ 65

2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid (1-methyl-1-phenylethyl)amide 1.95 410.2 [M − H]⁻ 66

2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid 2-methylsulfanylbenzylamide 1.95 428.1 [M − H]⁻ 67

2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid [2-(1H-indol-3-yl)ethyl]amide 1.87 435.2 [M − H]⁻

Examples 68–160

2Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid amides (Table 2)

Employing the procedure described above for Examples 4–67, the appropriate amine of Formula III (120 μL of a 0.33 M solution in NMP, 39.6 μmol) was reacted with 2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (200 μof a 0.20 M solution in NMP, 40.0 μmol) in the presence of i-Pr₂NEt (80 μL of a 0.50 M solution in NMP, 40.0 μmol). Following evaporation of the NMP, the residues were dissolved in DMSO (450 μL), before being subjected to preparative mass-directed liquid chromatographic purification to provide the compounds illustrated in Table 2.

TABLE 2 Example CHEMISTRY Name RT Base Peak 68

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic aciddibutylamide 2.01 405.2 [M + H]⁺ 69

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbutylethylamide 1.87 377.2 [M + H]⁺ 70

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidisopropylmethylamide 1.66 347.2 [M − H]⁻ 71

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbenzyl(2-hydroxyethyl)amide 1.65 425.2 [M − H]⁻ 72

6-(1,4-Dioxa-8-azaspiro[4.5]decane-8-sulfonyl)-4-trifluoromethyl-1H-quinolin-2-one 1.06 378.2 [M + H]⁺ 73

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidcyclopropylmethyl-propylamide 1.87 389.2 [M + H]⁺ 74

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-hydroxyethyl)-pentylamide 1.68 405.2 [M − H]⁻ 75

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidcyclohexylmethylamide 1.86 389.2 [M + H]⁺ 76

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbutylmethylamide 1.81 361.2 [M − H]⁻ 77

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-cyanoethyl)methylamide 1.49 358.2 [M − H]⁻ 78

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidmethylphenethylamide 1.86 411.2 [M + H]⁺ 79

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-suifonic acidbenzylethylamide 1.88 411.2 [M + H]⁺ 80

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbis(2-methoxyethyl)amide 1.57 409.1 [M + H]⁺ 81

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidpyridin-3-ylamide 1.34 370.1 [M + H]⁺ 82

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidm-tolylamide 1.73 381.1 [M − H]⁻ 83

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidp-tolylamide 1.71 381.1 [M − H]⁻ 84

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-fluorophenyl)amide 1.68 385.1 [M − H]⁻ 85

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2,5-dimethyl-2H-pyrazol-3-yl)amide 1.38 387.2 [M + H]⁺ 86

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-ethynylphenyl)amide 1.74 391.1 [M − H]⁻ 87

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-cyanophenyl)amide 1.62 392.1 [M − H]⁻ 88

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-ethylphenyl)amide 1.75 395.2 [M − H]⁻ 89

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-ethylphenyl)amide 1.80 395.2 [M − H]⁻ 90

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2,6-dimethylphenyl)amide 1.68 395.1 [M − H]⁻ 91

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-hydroxymethylphenyl)amide 1.46 397.2 [M − H]⁻ 92

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-methoxyphenyl)amide 1.63 397.1 [M − H]⁻ 93

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidquinolin-6-ylamide 1.30 420.2 [M + H]⁺ 94

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2,4-difluorophenyl)amide 1.69 403.1 [M − H]⁻ 95

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-cyanomethylphenyl)amide 1.55 406.1 [M − H]⁻ 96

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidindan-5-ylamide 1.81 407.2 [M − H]⁻ 97

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-isopropylphenyl)amide 1.85 409.2 [M − H]⁻ 98

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidbenzo[1,3]dioxol-5-ylamide 1.61 411.1 [M − H]⁻ 99

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-methylbiphenyl-3-yl)amide 1.92 457.2 [M − H]⁻ 100

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[3-(1-hydroxyethyl)phenyl]amide 1.47 411.1 [M − H]⁻ 101

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-methylsulfanylphenyl)amide 1.74 413.1 [M − H]⁻ 102

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2,5-dimethoxyphenyl)amide 1.65 427.1 [M − H]⁻ 103

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3,5-dimethoxyphenyl)amide 1.68 427.1 [M − H]⁻ 104

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)amide 1.60 429.2 [M + H]⁺ 105

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-isopropoxyphenyl)amide 1.80 425.2 [M − H]⁻ 106

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-difluoromethoxyphenyl)amide 1.72 433.1 [M − H]⁻ 107

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(5-phenyl-2H-pyrazol-3-yl)amide 1.63 435.1 [M + H]⁺ 108

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-methylcinnolin-5-yl)amide 1.46 435.1 [M + H]⁺ 109

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-trifluoromethylphenyl)amide 1.80 435.1 [M − H]⁻ 110

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-bromophenyl)amide 1.72 449.0 [M + H]⁺ 111

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(4-methyl-2-oxo-2H-chromen-7-yl)amide 1.62 449.1 [M − H]⁻ 112

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-trifluoromethoxyphenyl)amide 1.85 451.1 [M − H]⁻ 113

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[4-(2-hydroxyethyl)phenyl]amide 1.45 413.2 [M + H]⁺ 114

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-benzyloxyphenyl)amide 1.90 473.1 [M − H]⁻ 115

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-phenylsulfanylphenyl)amide 1.93 475.1 [M − H]⁻ 116

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-methoxyphenyl)amide 1.66 397.1 [M − H]⁻ 117

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidisopropylamide 1.43 333.1 [M − H]⁻ 118

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(thiophen-2-ylmethyl)amide 1.57 387.1 [M − H]⁻ 119

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-methoxyethyl)amide 1.31 392.1 [M + H +MeO]⁺ 120

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidcyclopentylamide 1.57 359.1 [M − H]⁻ 121

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-methylbutyl)amide 1.68 361.1 [M − H]⁻ 122

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3,3-dimethylbutyl)amide 1.73 375.2 [M − H]⁻ 123

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidcyclohexylmethylamide 1.77 387.2 [M − H]⁻ 124

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-methylbenzylamide 1.63 395.1 [M − H]⁻ 125

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(1-phenylethyl)amide 1.62 395.1 [M − H]⁻ 126

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidcycloheptylamide 1.72 387.2 [M − H]⁻ 127

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-isopropoxypropyl)amide 1.53 391.2 [M − H]⁻ 128

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidphenethylamide 1.63 395.2 [M − H]⁻ 129

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid4-fluorobenzylamide 1.59 399.1 [M − H]⁻ 130

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acidindan-1-ylamide 1.72 407.2 [M − H]⁻ 131

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-phenylpropyl)amide 1.74 409.2 [M − H]⁻ 132

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-cyclohex-1-enylethyl)amide 1.79 399.2 [M − H]⁻ 133

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-thiophen-2-ylethyl)amide 1.64 401.1 [M − H]⁻ 134

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(1-methylpyrrolidin-2-yl)ethyl]amide 1.07 404.2 [M + H]⁺ 135

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(2-methoxyphenyl)ethyl]amide 1.66 425.1 [M − H]⁻ 136

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-ethoxybenzylamide 1.73 425.2 [M − H]⁻ 137

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid5-fluoro-2-methylbenzylamide 1.68 413.1 [M − H]⁻ 138

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid3-chlorobenzylamide 1.68 415.1 [M − H]⁻ 139

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2,6-difluorobenzylamide 1.60 417.1 [M − H]⁻ 140

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-chloro-4-fluorobenzylamide 1.69 433.1 [M − H]⁻ 141

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid3-chloro-2-fluorobenzylamide 1.66 433.1 [M − H]⁻ 142

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-chloro-6-fluorobenzylamide 1.62 433.1 [M − H]⁻ 143

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-methylsulfanylbenzylamide 1.68 427.1 [M − H]⁻ 144

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-chloro-6-methylbenzylamide 1.68 429.1 [M − H]⁻ 145

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2,3-difluoro-4-methylbenzylamide 1.65 431.1 [M − H]⁻ 146

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid5-chloro-2-fluorobenzylamide 1.68 433.1 [M − H]⁻ 147

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(1H-indol-3-yl)ethyl]amide 1.60 436.1 [M + H]⁺ 148

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-hydroxy-methylbicyclo[2.2.1]hept-2-yl) 1.44 415.2 [M − H]⁻ 149

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid3,5-dimethoxybenzylamide 1.59 484.1 [M + H +MeO]⁺ 150

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(4-fluorophenyl)-1,1-dimethylethyl]amide 1.83 484.2 [M + H +MeO]⁺ 151

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-difluoromethoxybenzylamide 1.66 447.1 [M − H]⁻ 152

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-chloro-6-fluoro-3-methylbenzylamide 1.72 447.1 [M − H]⁻ 153

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-trifluoromethylbenzylamide 1.75 449.1 [M − H]⁻ 154

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid[2-(2-chloro-6-fluorobenzylsulfanyl)ethyl]amide 1.82 493.1 [M − H]⁻ 155

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-(2-hydroxymethyl-phenylsulfanyl)benzylamide 1.68 519.1 [M − H]⁻ 156

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-bromobenzylamide 1.70 461.0 [M − H]⁻ 157

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(3-hydroxypropyl)amide 1.21 351.1 [M + H]⁺ 158

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid2-fluoro-5-trifluoromethylbenzylamide 1.70 467.1 [M − H]⁻ 159

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2,2-diphenylethyl)amide 1.84 471.2 [M − H]⁻ 160

2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid(2-benzyloxycyclohexyl)amide 1.82 522.2 [M + H +MeO]⁺

Example 162 Biological Data

The compounds ability to antagonize the effects of androgen on the androgen receptor were determined in the protocol described immediately below. The results are shown in Table 3.

Experimental Procedure for AR Antagonist Cell Assay

Cell line: MDA-MB453-MMTV clone 54-19. This cell line is a stable transfected cell line with MDA-MB453 cell background (human breast tumor cell expressing high level of androgen receptor). A MMTV minimal promoter containing ARE was first cloned in front of a firefly luciferase reporter gene. Then the cascade was cloned into transfection vector pUV120puro. Electroporation method was used for transfecting MDA-MB-453 cell. Puromycin resistant stable cell line was selected.

Cell Culture Media and Reagents:

Culture medium: DMEM (high glucose, Gibco cat #: 11960-044), 10% FBS, and 1% L-glutamine

Plating medium: DMEM (phenol red free), 10% charcoal treated HyClone serum, 1% L-glutamine

Assay medium: DMEM (phenol red free), 1% charcoal treated HyClone serum, 1% L-glutamine, and 1% penicillin/streptomycin

3× luciferase buffer: 2% beta-mercaptoethanol, 0.6% ATP, 0.0135% luciferine in cell lysis buffer

Assay Procedure:

-   1. Cells are maintained in culture medium, splitting cells when they     reach 80–90% confluence -   2. To test compounds, 10,000 cells/well are plated to opaque 96 cell     culture plate in 100 ul/well plating medium, culture for overnight     at 37° C. in cell culture incubator -   3. Carefully remove plating medium, then add 80 ul/well of     pre-warmed assay medium, add 10 ul/well testing compound (final     concentration at 10 uM or 1 uM), incubate at 37° C. for 30 minutes -   4. Add 10 ul/well freshly prepared DHT (final concentration at 100     pM) to each well, incubate at 37° C. for 17 hr (overnight) -   5. Add 50 ul/well 3× luciferase buffer, incubate at room temperature     for 5 minutes, then count on Luminometer     The fold induction over background by 100 pM DHT in the absence of     testing compounds is standardized as 100% and experimental result is     expressed as percentage of inhibition by testing compounds.     TABLE3

Example IC50 (uM)  12 >10  13 0.76  14 1.03  15 1.17  16 5.03  17 0.87  18 >10  19 >10  20 >10  21 0.99  22 4.47  23 >10  24 4.23  25 8.61  26 4.04  27 0.84  28 >10  29 3.72  30 >10  31 1.32  32 >10  33 >10  34 >10  35 >10  36 2.72  37 6.1  38 5.63  39 0.93  40 >10  41 3.86  42 >10  43 >10  44 3.76  45 >10  46 >10  47 2.96  48 1.13  49 >10  50 1.55  51 >10  52 >10  53 1.84  54 5.68  55 4.31  56 2.73  57 >10  58 5.4  59 >10  60 6.33  61 1.53  62 3.92  63 >10  4 10.6  5 >10  6 >10  7 >10  8 >10  9 >10  10 6.35  11 10  64 >10  65 >10  66 >10  67 >10 143 0.84 136 0.58 156 2.16 145 >10 140 5.65 153 0.75 141 >10 151 0.73 159 1.56 144 5.53 149 >10 146 6.54 152 >10 127 1.60 125 2.94 118 >10 158 6.61 147 0.26 142 2.39 160 >10 122 1.03 119 4.69 154 2.18 123 8.51 155 1.94 126 2.93 120 0.82 157 6.73 124 4.61 128 2.65 133 1.90 138 >10 129 >10 135 0.17 137 3.76 139 2.98 132 0.21 131 0.35 130 1.03 117 2.34 121 0.28 150 1.83 148 2.26 134 >10  71 1.31  73 0.55  75 5.72  76 0.21  77 1.04  80 >10  68 0.41  69 0.20  70 0.55  74 0.29  79 0.39  78 0.15  81 >10  82 0.83  83 1.14  84 7.08  85 >10  86 0.45  87 3.55  88 0.13  89 0.36  90 >10  91 3.13  92 >10  93 3.46  94 >10  95 0.84  96 0.14  97 0.20  98 >10  99 >10 100 >10 101 0.36 102 7.86 103 0.2 104 >10 105 0.45 106 0.26 107 >10 108 >10 109 0.21 110 >10 111 >10 112 0.12 113 >10 114 >10 115 8.13 116 0.34  72 >10 

1. A compound of the formula:

or a pharmaceutically acceptable salt or solvate thereof, in which: a. M is NZ or O; b. Z is represented by H or (C₁–C₄)alkyl; c. R¹ is represented by (C₁–C₂)alkyl, optionally substituted with one or more halogens, or (C₁–C₂)alkoxy, optionally substituted with 1 or more halogens; d. R² is absent, or may represent up to 2 substituents selected from the group consisting of halogen, nitrile, hydroxy, (C₁–C₄)alkyl, (C₂–C₄)alkenyl, (C₂–C₄)alkynyl, (C₁–C₄)alkoxy, (C₁–C₂)alkyl substituted with 1 or more halogens, (C₁–C₂)alkoxy substituted with one or more halogens, SR⁴, and NR⁴R⁵; e. R⁴ is represented by hydrogen, optionally substituted phenyl, (C₁–C₄)alkyl, or optionally substituted benzyl; f. R⁵ is represented by optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclic g. A and B are each independently represented by a substituent selected from the group consisting of hydrogen, (C₁–C₆)alkyl optionally substituted with one or more halogens, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, optionally substituted (C₃–C₈) cycloalkyl, optionally substituted (C₅–C₈) cycloalkenyl, optionally substituted phenyl, optionally substituted cycloalkylphenyl, optionally substituted heterocyclic, optionally substituted heteroaryl, (C₁–C₆)alkylR⁶, —(CH₂)_(m)—R⁷—Y[—CH₂]_(n)—X—R⁸, and —(CH₂)_(q)CHX¹X²; h. R⁶ is represented by a substituent selected from the group consisting of nitrile, OH, optionally substituted phenyl, optionally substituted cyloalkylphenyl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted (C₃–C₈) cycloalkyl, optionally substituted (C₅–C₈) cycloalkenyl, SR⁴, and NR⁴R⁵; i. R⁷ is absent, or is represented by a substituent selected from the group consisting of optionally substituted (C₃–C₈) cycloalkyl, optionally substituted (C₅–C₈) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, and optionally substituted phenyl; j. R⁸ is absent, or is represented by a substituent selected from the group consisting of (C₁–C₆)alkyl optionally substituted with one, or more, halogens, optionally substituted (C₃–C₈) cycloalkyl, optionally substituted (C₅–C₈) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted phenyl, and optionally substituted cycloalkylphenyl; k. m is an integer selected from 0, 1, 2, 3, or 4; l. Y is absent, or is represented by O, C(O), C(O)O, CH₂C(O)O, OH, SH, or S; m. n is represented by an integer selected from 0, 1, 2, 3, or 4; n. X is absent, or is represented by O, C(O), C(O)O, CH₂C(O)O, OH, SH, or S; o. q is represented by an integer selected from 0, 1, 2, 3, or 4; p. X¹ is represented by a substituent selected from the group consisting of optionally substituted (C₃–C₈) cycloalkyl, optionally substituted (C₅–C₈) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted phenyl, and optionally substituted cycloalkylphenyl, and; q. X² is represented by a substituent selected from the group consisting of optionally substituted (C₃–C₈) cycloalkyl, optionally substituted (C₅–C₈) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted phenyl, and optionally substituted cycloalkylphenyl.
 2. A compound according to claim 1 in which R¹ is represented by trifluoromethyl.
 3. A compound according to claim 2 in which M is NZ.
 4. A compound according to claim 2 in which B is hydrogen.
 5. A compound according to claim 4 in which A is represented by optionally substituted phenyl.
 6. A compound according to claim 5 in which said phenyl is substituted with a substituent selected from the group consisting of meta (C₁–C₄)alkyl and meta (C₁–C₂)alkoxy substituted with one or more halogen atoms.
 7. A compound according to claim 4 in which A is (C₁–C₄)alkyl.
 8. A compound according to claim 4 in which A is C₁–C₆alkylR⁶ and R⁶ is cycloalkenyl.
 9. A compound according to claim 8 in which A is represented by cyclopentenylethyl.
 10. A pharmaceutical composition comprising a compound according to claim 1 in admixture with 1, or more, pharmaceutically acceptable excipients.
 11. A topical pharmaceutical formulation comprising a compound according to claim 1 in admixture with 1, or more, pharmaceutically acceptable excipients suitable for dermal application.
 12. A compound according to claim 1 selected from the group consisting of: 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid phenylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid phenylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid benzylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid butylethylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid butyl(2-hydroxyethyl)-amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid benzyl(2-hydroxyethyl)-amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-hydroxyethyl)-pentylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid butylmethylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid dibenzylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid benzylethylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid methylphenethylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid methylphenylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid m-tolylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid p-tolylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-ethynylphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-ethylphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-ethylphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2,6-dimethylphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-hydroxymethylphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-methoxyphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-cyanomethylphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid indan-5-ylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid indan-4-ylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-acetylphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-isopropylphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid benzo[1,3]dioxol-5-ylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-methylbiphenyl-3-yl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydro-quinoline-6-sulfonic acid [3-(1-hydroxyethyl)phenyl]-amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-methylsulfanylphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (5-fluoro-2-methylphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-chlorophenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid isoquinolin-3-ylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid quinolin-3-ylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid quinolin-8-ylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-cyano-5-methylsulfanyl-2H-pyrazol-3-yl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3,5-dimethoxyphenyl)-amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-isopropoxyphenyl)-amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-difluoromethoxy-phenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-trifluoromethylphenyl)-amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-methyl-2-oxo-2H-chromen-7-yl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-trifluoromethoxy-phenyl)amide; [4-(1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonylamino)phenyl]acetic acid ethyl ester; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-benzylphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-ethoxyphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3,5-di-tert-butylphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid benzyl(4-methoxy-phenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid [4-(3-trifluoromethylpyrazol-1-yl)phenyl]amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-methoxyphenyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3,3-dimethylbutyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid phenethylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 4-methylbenzylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-methylbenzylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-cyclohex-1-enylethyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-thiophen-2-ylethyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid indan-1-ylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-phenylpropyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-phenylbutyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid [2-(2-methoxyphenyl)ethyl]amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 5-chloro-2-fluorobenzylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid [2-(1H-indol-3-yl)ethyl]amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-tert-butylsulfanylethyl)amide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-trifluoromethyl-benzylamide; 1-Methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid [2-(2-chloro-6-fluorobenzylsulfanyl)ethyl]-amide; 2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid (pyridin-3-ylmethyl)amide; 2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid (1-methyl-1-phenylethyl)amide; 2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid 2-methylsulfanylbenzylamide; 2-Oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid [2-(1H-indol-3-yl)ethyl]amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid dibutylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid butylethylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid isopropylmethylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid benzyl(2-hydroxyethyl)amide; 6-(1,4-Dioxa-8-azaspiro[4.5]decane-8-sulfonyl)-4-trifluoromethyl-1H-quinolin-2-one; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid cyclopropylmethyl-propylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-hydroxyethyl)-pentylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid cyclohexylmethylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid butylmethylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-cyanoethyl)methylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid methylphenethylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid benzylethylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid bis(2-methoxyethyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid pyridin-3-ylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid m-tolylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid p-tolylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-fluorophenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2,5-dimethyl-2H-pyrazol-3-yl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-ethynylphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-cyanophenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-ethylphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-ethylphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2,6-dimethylphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-hydroxymethylphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-methoxyphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid quinolin-6-ylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2,4-difluorophenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-cyanomethylphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid indan-5-ylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-isopropylphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid benzo[1,3]dioxol-5-ylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-methylbiphenyl-3-yl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid [3-(1-hydroxyethyl)phenyl]amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-methylsulfanylphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2,5-dimethoxyphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3,5-dimethoxyphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-isopropoxyphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-difluoromethoxyphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (5-phenyl-2H-pyrazol-3-yl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-methylcinnolin-5-yl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-trifluoromethylphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-bromophenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (4-methyl-2-oxo-2H-chromen-7-yl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-trifluoromethoxyphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid [4-(2-hydroxyethyl)phenyl]amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-benzyloxyphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-phenylsulfanylphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-methoxyphenyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid isopropylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (thiophen-2-ylmethyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-methoxyethyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid cyclopentylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-methylbutyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3,3-dimethylbutyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid cyclohexylmethylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-methylbenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (1-phenylethyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid cycloheptylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-isopropoxypropyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid phenethylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 4-fluorobenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid indan-1-ylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-phenylpropyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-cyclohex-1-enylethyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-thiophen-2-ylethyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid [2-(1-methylpyrrolidin-2-yl)ethyl]amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid [2-(2-methoxyphenyl)ethyl]amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-ethoxybenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 5-fluoro-2-methylbenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 3-chlorobenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2,6-difluorobenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-chloro-4-fluorobenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 3-chloro-2-fluorobenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-chloro-6-fluorobenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-methylsulfanylbenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-chloro-6-methylbenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2,3-difluoro-4-methylbenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 5-chloro-2-fluorobenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid [2-(1H-indol-3-yl)ethyl]amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-hydroxymethylbicyclo[2.2.1]hept-2-yl); 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 3,5-dimethoxybenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid [2-(4-fluorophenyl)-1,1-dimethylethyl]amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-difluoromethoxybenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-chloro-6-fluoro-3-methylbenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-trifluoromethylbenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid [2-(2-chloro-6-fluorobenzylsulfanyl)ethyl]amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-(2-hydroxymethylphenylsulfanyl)benzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-bromobenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (3-hydroxypropyl)amide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid 2-fluoro-5-trifluoromethylbenzylamide; 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2,2-diphenylethyl)amide; and 2-Oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonic acid (2-benzyloxycyclohexyl)amide. 